Field of the Invention
The present invention provides a convenient and accurate diagnostic method for pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorder associated with streptococci infection (PANDAS). The ability to reliably diagnose PANS and/or PANDAS using such a method allows treating clinicians to prescribe treatments in a more effective and timely manner than currently possible. Such ability to reliably diagnose PANS and PANDAS is expected to allow significant improvement in the outcomes of many patients with PANS and/or PANDAS.
Description of the Related Art
Pediatric autoimmune neuropsychiatric disorder associated with streptococci infection (PANDAS) is a sudden and severe onset obsessive-compulsive disorder (OCD) or tic disorder described in 1998 (Swedo et al., Am. J. Psychiatry 155:2, 264-271 (1998)). Such disorders generally have an onset between the ages of about 2 to 14. There are currently five diagnostic criteria required for a PANDAS diagnosis:
(1) presence of OCD or tic disorder;
(2) prepubertal symptom onset;
(3) acute symptom onset and episodic (relapsing-remitting) course;
(4) temporal association of Group A streptococcal infection and symptom onset/exacerbations; and
(5) association with neuropsychiatric abnormalities (especially hyperactivity and choreiform movements). Swedo et al., Pediatr. Therapeut. 2012, 2:2.
More recently, pediatric acute-onset neuropsychiatric syndrome (PANS) has been described based on three diagnostic criteria:
(1) abrupt, dramatic onset of obsessive-compulsive disorder or severely restricted food intake;
(2) concurrent presence of additional neuropsychiatric symptoms, with
similarly severe and acute onset, from at least two of the following seven categories:                (a) anxiety;        (b) motional lability and/or depression;        (c) irritability, aggression and/or severely oppositional behaviors;        (d) behavioral (developmental) regression;        (e) deterioration in school performance;        (f) sensory or motor abnormalities; or        (g) somatic signs and symptoms, including sleep disturbances, enuresis or urinary frequency; and        
(3) symptoms not better explained by a known neuropsychiatric or medical disorder (e.g., Sydenham chorea, systemic lupus erythematosus, Tourette disorder or the like). Id. Generally PANDAS, which has a temporal association of Group A streptococcal infection, is a subset of the more general PANS condition.
Some of most striking aspects of PANS/PANDAS include its rapid onset and the severity and variability of its neuropsychiatric abnormalities. Many parents can point to a particular day or week when the condition began, often describing the event as “falling off a cliff” or the “day they lost their child.” A recent posting from the International OCD Foundation described the PANDAS experience as follows:
‘My child was fine last week, last month—and now I have lost her. This is not my child; what has happened??? What do I do??’
“For every parent of a child with an illness, especially a mental illness, there is a particular story. But when you meet a parent of a child with PANDAS (typically a child between ages 3-14), you will hear the same panicked story over and over. A child who was happy at home and at school, and was social and athletic, is now walking in circles for hours, washing hands until they bleed, asking the same questions over and over—and over. A child that used to be comforted by a hug is now inconsolable. They may be begging parents for help, begging for a way to end the horror that exists only in their minds. Imagine a child screaming in terror in a corner, and a parent unable to hold them. These parents will tell you in detail about the day or week that their child changed. Here is what life looks like now—children may exhibit some or all of these symptoms:
Acute sudden onset of OCD
Challenges with eating, and at the extreme end, anorexia
Sensory issues such as sensitivity to clothes, sound, and light
Handwriting noticeably deteriorates
Urinary frequency or bedwetting
Small motor skills deteriorate—a craft project from yesterday is now impossible to complete . . .
Tics
Inattentive, distractible, unable to focus and has difficulties with memory
Overnight onset of anxiety or panic attacks over things that were no big deal a few days ago, such as thunderstorms or bugs
Suddenly unable to separate from their caregiver, or to sleep alone
Screaming for hours on end
Fear of germs and other more traditional-looking OCD symptoms”
“You will often find these parents on the computer every night, desperate for an explanation that makes sense. They are seeking specialists who can help—and finding no answers. They are starting to feel crazy themselves, because no one seems to believe what they are going through.” Jenike and Dailey, International OCD Foundation (2012).
Thus, parents turning to the medical community are often at a loss since currently there are no clinical methods or tests to provide or confirm a diagnosis. Currently, only diagnosis based on existing observational clinical criteria are possible. Children presenting with neuropsychiatric symptoms would not generally be considered candidates for the most aggressive treatment options (e.g., autoimmune therapeutics or immune modulation treatments discussed below) without a diagnostic tool that shows autoimmune results. This is why there is significant difficulty in making a PANDAS/PANS diagnosis based upon symptoms alone; indeed, there is even difficulty in agreeing upon standard nomenclature for such conditions.
Effective treatments for PANDAS/PANS are available. During the early stages with bacterial infections, antibiotic therapy, perhaps even for several months, is recommended. Antibiotics (e.g., amoxicillin, penicillin, azithromycin, and cephalosporins) can be used to treat the strep infection in PANDAS and often result in immediate improvement. Treatment with other anti-infective agents may also be useful in some cases depending on the specific infection observed in particular cases. For purposes of this invention, antibiotic therapy is to include treatment with both antibiotics and other anti-infective agents.
Treatment with anti-inflammatory agents (including both steroids and non-steroidal anti-inflammatory drugs (NSAIDS)) may also be helpful. Treatment with prednisone or corticosteroids has been used with some reports of improvements. In some cases, however, tic conditions have actually worsened. Such treatments can only be used for short time periods due to possible serious long-term complications. And even where improvements are observed, symptoms often return after termination of treatment—sometimes to even worse levels. Nonetheless, since a “steroid response” may be an indication that immune-based therapies may be helpful.
Where symptoms lasting more than a year or very severe disease, intravenous immunoglobulin (IVIG) or plasmapheresis (i.e., plasma exchange to remove antibodies from the blood) may be helpful. A clinical study is currently being conducted using IVIG therapy with Gamunex®-C (Grifols Therapeutics), an intravenous immunoglobulin therapy (IVIG). In the worst cases, treatment with rituximab (Rituxan® from Genentech or MabThera® from Roche) may be suggested; rituximab is a chimeric monoclonal antibody against the protein CD20 normally used to treat non-Hodgkin's lymphoma). Such treatments are considered experimental for treatment of PANDAS/PANS and, thus are generally not covered by medical insurance. And such treatments can be very expensive—$50,000 or higher in some cases. Moreover, significant side effects—up to, and including, death—can result from such treatments.
The lack of clinical methods or tests to provide or confirm a PANS or PANDAS diagnosis presents significant obstacles to providing effective therapies to children suffering from PANS or PANDAS and their parents seeking such therapies. A physician, without such clinical methods or tests, may be less likely to conclude such a diagnosis simply based on the currently existing observational clinical criteria. After all, such current treatments regimes can be uncertain in outcome, expose the patient to significant side effects as well as long term, painful, and difficult procedures, and expose the parents to very high economic costs. Clinical methods and procedures to more accurately diagnose PANS or PANDAS will more easily allow physicians to arrive at such diagnosis with confidence and will, over time, allow treatments to move out of the experimental phase and to achieve insurance coverage.
Thus, there remains a need to provide such clinical methods and procedures. Indeed, this need has been unmet since the first identification of PANDAS/PANS in the 1980s and remains unmet today. The present invention provides such methods.